Loria has disclosed that dehydroepiandrosterone, androst-5-ene-3.beta.,17.beta.-diol (AED) and androst-5-ene-3.beta.,7.beta.,17.beta.-triol (AET) are effective as enhancers of immune response (U.S. Pat. Nos. 5,077,284 and 5,206,008, incorporated herein by reference in their entirety). AED and AET have been shown to buffer the effects of hydrocortisone by counteracting the suppressive effects of hydrocortisone on lymphocyte proliferation. Furthermore, under infectious disease conditions, both AED and AET positively enhance lymphocyte proliferation and differentiation of cells.
In vertebrates the development of host protection against pathogens requires a selective host immune response that involves the mobilization of the humoral and/or cellular mediated immune responses. Several factors adversely affect the body's protective response capability by causing prolonged immuno-suppression or "down-regulation" of the immune system. It is, in reality, more appropriate to speak of "mal-regulation" or "deregulation" of the immune system than of "down-regulation" since the result is a failure to protect the body from assault or over-reaction to its immune response. Immuno-suppression provides an opportunity for pathogens to grow in the host. It does not matter what causes the primary insult to immunity. The resulting inability to muster the appropriate immune response has the same effect. Among the many different causes of immuno-suppression are viral, bacterial, fungal, yeast and parasitic infections, chemotherapy, irradiation, severe stress, chronic fatigue syndrome, diabetes mellitus, autoimmune diseases, and some forms of steroid therapy.
It has long been known that patients receiving steroid hormones of adrenocortical origin at pharmacologically appropriate doses show increased incidence of infectious disease. A. S. Fauci, immunolo. rev. 65, 133-155 (1982); and J. E. Parillo and A. S. Fauci, Annual Review of Pharmacology and Toxicology 19, 179-201 (1979). Dehydroepiandrosterone, also known as 3-.beta.-hydroxyandrost-5-en-17-one or dehydroiso-androsterone (referred to hereinafter as DHEA), is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones found in mammals. M. E. Windholz, The Merck Index, Ninth Edition (1976); K. Diem and C. Lentner, Geigy Scientific Tables (1975). (Although DHEA appears to serve as an intermediary in gonadal steroid synthesis, the primary physiological function of DHEA has not been fully understood. It has been known, however, that levels of this hormone begin to decline in the second decade of life, reaching 5% of the original level in the elderly.)
The above-referenced U.S. Pat. No. 5,077,284 entitled "Use of Dehydroepiandrosterone to Improve Immune Response" describes the subcutaneous or oral administration of DHEA to improve the host's response to infections. U.S. Pat. No. 4,978,532 describes use of patch technology to deliver DHEA.
DHEA is a precursor in a metabolic pathway which ultimately leads to more powerful agents that increase immune response in mammals. That is, DHEA acts as a biphasic compound: it acts as an immuno-modulator when converted to androstenediol (androst-5-ene-3.beta.,17.beta.-diol, .beta.AED) or androstenetriol (androst-5-ene-3.beta.,7.beta.,17.beta.-triol, .beta.AET). However, in vitro DHEA has certain lymphotoxic and suppressive effects on cell proliferation prior to its conversion to .beta.AED and/or .beta.AET. It is, therefore, postulated that the superior immunity enhancing properties obtained by administration of DHEA result from its conversion to more active metabolites.
Regulation of the immune system using the active agents of the invention would make it possible to more safely use chemotherapeutic agents. It has previously been disclosed in the aforementioned U.S. Pat. No. 5,206,008 that .beta.AED and .beta.AET (asteroid found in the skin, other epithelial tissue and neuronal tissue) enhance immune response and lymphocytic cell proliferation.
Androsta-5,7-diene-3.beta.,17.beta.-diol has been prepared from androst-5-ene-3.beta.,7.beta.,17.beta.-triol by Butenandt et al., Berichte, 71, 1316-1322 (1938) at page 1321, which is incorporated herein by reference in its entirety. Androsta-5,7-diene-3.beta.,17.beta.-diol was also prepared from androst-5-ene-3.beta.,17.beta.-diol by Milas et al., J. Am. Chem. Soc., 68, 738-40 (1946). Both Butenandt and Milas prepared the compound for the purpose of investigating whether it would exhibit antirachitic activity, but no activity was found by either investigator. Butenandt also examined the sex hormone properties of androsta-5,7-diene-3.beta.,17.beta.-diol and determined that it was slightly active in the capon comb test for androgenic activity and also slightly active when used in the immature female rat vagina test for estrogenic activity. Both activity levels were about 1/10 the corresponding activities of androst-5-ene-3.beta.,17.beta.-diol (AED), which in turn has been considered to have very weak androgenic and estrogenic properties. Further, Butenandt and Milas neither investigated nor suggested that androsta-5,7-diene-3.beta.,17.beta.-diol might have any practical medicinal applications. In fact, Butenandt concluded that androsta-5,7-diene-3.beta.,17.beta.-diol had no significant physiological activity.